This invention relates generally to pharmaceutical preparations and more specifically to dosage preparations which provide rapid dissolution and increased bioavailability of drugs having low water solubility. The preparations also have good drug content uniformity.
Many useful drugs have water solubilities of about 1 part by weight per 100 parts by weight of water (10,000 mcg/ml) or less at 25.degree. C. which can result in poor drug absorption and bioavailability. Many of these drugs are used in low doses (50 mg or less) and it is difficult to obtain good drug content uniformity especially in tablet dosage forms prepared by dry blending and direct compression.
The diuretic and antihypertensive agent metolazone is a sulfonamide derivative. Its chemical name is 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone, and it is described in U.S. Pat. No. 3,360,518 which is incorporated by reference. Metolazone has a water solubility of approximately 60.3 mcg/ml at 25.degree. C. and 100.0 mcg/ml at 36.degree. C. A problem associated with dosage forms of metolazone is its poor dissolution characteristics, which is caused by poor water solubility. Burger et al., Drug Research, 25, 24 (1975) reported the intrinsic solution rate of five different solid forms of metolazone in n-butanol, water and 0.01N hydrochloric acid. The amorphous and metastable metolazone of softening temperature 140.degree.-155.degree. C. was observed to dissolve about 8 times faster than in 0.01N hydrochloric acid than the stable modification (mp. 267.degree.-270.degree. C.). On account of the metastable nature of the more soluble polymorphic forms, as well as the inconsistency with their manufacture, they are unsuitable for practical use. Accordingly, dosage forms of stable metolazone and other drugs of low water solubility having improved dissolution characteristics, good drug uniformity, and which are easily manufactured are desired because they would be expected to make the drug more bioavailable. Better bioavailability could permit a smaller dosage of drug to be used and consequently reduce side effects such as hypokalemia or abnormally low potassium levels in the blood which result from metalozone usage. I have now discovered dosage forms of poorly absorbed drugs which provide a dramatic increase in dissolution rates and which can be readily manufactured to provide good drug uniformity especially in dosages containing less than 50 mg of the drug.
The improved result is obtained by using certain excipient mixtures and providing the drug in the form of fine particles.